The goal of this ongoing project is to continue the development of fetal cardiac surgery. Certain congenital defects are uncorrectable after birth and there is a clear advantage for intrauterine corrective surgery. This approach requires an understanding of the physiological effects of surgical intervention and extracorporeal circulation on the fetus. Our work in this area to date has allowed us to gain a substantial by incomplete understanding of these issues. The three major pathophysiological responses which limit fetal survival following intervention and extracorporeal circulation (which we identified in the original grant proposal) include: 1. The loss of fetal cardiovascular homeostasis in the pre-bypass phase of fetal intervention. 2. The "step function" rise in fetal vascular resistance at the institution of fetal bypass which is associated with acute decompensation. 3. The gradual rise in placental vascular resistance during and after fetal bypass which results in depressed placental blood flow. The specific focus of this project remains as stated in the original proposal, to identify the mediators of detailed pathophysiological mechanisms of these three responses with an eye towards clinical application of this information to advance the development of human fetal cardiac surgery. Each of these three responses will be systematically evaluated. Experiments examining the pre-bypass problem will focus on the role of the fetal stress response. Further understanding of this response is presently limited by our fetal animal model (sheep). We propose to study the efficacy of narcotic anesthesia in blunting the stress response in an instrumental primate model. Experiments addressing the 'step function' rise in fetal vascular resistances will examine the inhibition of this response using specifically designed bypass circuitry. Our methodology will include ultrasonic flow transducers to continuously measure instantaneous changes in organ flow in addition to our more specific microsphere techniques which do not have this capability. In recognition of the multiple factors effecting the placental vasculature, experiments addressing the gradual rise in post bypass placental resistance will examine the role of placental vascular dysfunction in addition to the role of eicosanoids.